Amino alcohol derivatives for the treatment of demyelinating peripheral neuropathies

Abstract

The invention provides the use of compound of formula V or formula VI in the treatment of a demyelinating peripheral neuropathy: wherein X, R 1 , R 2 , R 3 , R 4 , R 5 , n, R 1a , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , X a and n a are defined herein; or the N-oxide derivatives thereof or prodrugs thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof. The invention further provides combinations of a compound of Formula V or VI with one or more therapeutic agents and pharmaceutical composition thereof.

1 . A method of treating a subject having a demyelinating peripheral neuropathy comprising administering to the subject an effective amount of a compound of formula V or formula VI: 
       
         
           
           
               
               
           
         
         wherein X is O, S, SO or SO 2 , 
         R 1  is halogen, trihalomethyl, OH, C 1-7 alkyl, C 1-4 alkoxy, trifluoromethoxy, phenoxy, cyclohexylmethyloxy, pyridylmethoxy, cinnamyloxy, naphthylmethoxy, phenoxymethyl, CH 2 —OH, CH 2 —CH 2 —OH, C 1-4 alkylthio, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, benzylthio, acetyl, nitro or cyano, or phenyl, phenylC 1-4 alkyl or phenyl-C 1-4 alkoxy each phenyl group thereof being optionally substituted by halogen, CF 3 , C 1-4 alkyl or C 1-4 alkoxy; 
         R 2  is H, halogen, trihalomethyl, C 1-4 alkoxy, C 1-7 alkyl, phenethyl or benzyloxy; 
         R 3  is H, halogen, CF 3 , OH, C 1-7 alkyl, C 1-4 alkoxy, benzyloxy, phenyl or C 1-4 alkoxymethyl; 
         each of R 4  and R 5 , independently is H or a residue of formula (a) 
       
       
         
           
           
               
               
           
         
         wherein each of R 8  and R 9 , independently, is H or C 1-4 alkyl optionally substituted by halogen; and 
         n is an integer from 1 to 4; 
         and the N-oxide derivatives thereof or prodrugs thereof, 
         or a pharmaceutically acceptable salt, solvate or hydrate thereof; 
       
       
         
           
           
               
               
           
         
         wherein 
         R 1a  is halogen, trihalomethyl, C 1-4 alkoxy, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, aralkyl, optionally substituted phenoxy or aralkyloxy; 
         R 2a  is H, halogen, trihalomethyl, C 1-4 alkyl, C 1-4 alkoxy, aralkyl or aralkyloxy; 
         R 3a  is H, halogen, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio or benzyloxy; 
         R 4a  is H, C 1-4 alkyl, phenyl, optionally substituted benzyl or benzoyl, or lower aliphatic C 1-5 acyl; 
         R 5a  is H, monohalomethyl, C 1-4 alkyl, C 1-4 alkoxy-methyl, C 1-4 alkyl-thiomethyl, hydroxyethyl, hydroxypropyl, phenyl, aralkyl, C 2-4 alkenyl or -alkynyl; 
         R 6a  is H or C 1-4 alkyl; 
         R 7a  is H, C 1-4 alkyl or a residue of formula (a) as defined above, 
         X a  is O, S, SO or SO 2 ; 
         n a  is an integer of 1 to 4; and 
         * designates a chiral centre of (R) or (S) configuration and the formula includes racemic and other mixtures of (R) and (S) configuration molecules; 
         and the N-oxide derivatives thereof or prodrugs thereof, 
         or a pharmaceutically acceptable salt, solvate or hydrate thereof. 
       
     
     
         2 . The method of  claim 1 , wherein the neuropathy is Guillain-Barré syndrome. 
     
     
         3 . The method of  claim 1 , wherein the neuropathy is chronic inflammatory demyelinating polyradiculoneuropathy. 
     
     
         4 . The method of  claim 1 , wherein the neuropathy is multifocal motor neuropathy with conduction block. 
     
     
         5 . The method of  claim 1 , wherein the neuropathy is paraproteinaemic demyelinating peripheral neuropathy. 
     
     
         6 . The method of  claim 1  wherein the compound is of formula V. 
     
     
         7 . The method of  claim 6  wherein the compound is of formula Va: 
       
         
           
           
               
               
           
         
         wherein 
         R 2 , R 3 , R 4 , R 5 , and n are as defined in  claim 1 ; and Y is O or S and 
         R 6  is hydrogen, halogen, C 1-7 alkyl, C 1-4 alkoxy or trifluoromethyl. 
       
     
     
         8 . The method of  claim 1  wherein the compound is of formula VI. 
     
     
         9 . The method of  claim 8  wherein the compound is of formula VIa: 
       
         
           
           
               
               
           
         
         where the symbols are as defined in  claim 1 . 
       
     
     
         10 . The method of  claim 8 , wherein R 2a  is H or halogen; R 3a  is H or halogen; R 4a  is H; R 5a  is C 1-4 alkyl; R 6a  is H; R 7a  is H; and n a  is 2. 
     
     
         11 . The method of  claim 1 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
         wherein * designates a chiral centre of (R) or (S) configuration and the formula includes racemic and other mixtures of (R) and (S) configuration molecules. 
       
     
     
         12 . The method of  claim 1 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         13 . (canceled) 
     
     
         14 . A method of alleviating a symptom of, delaying the progression of, or prolonging time to relapse of a demyelinating peripheral neuropathy comprising administering to the subject an effective amount of a compound having a structure defined in  claim 1 . 
     
     
         15 . A method of improving or maintaining, or delaying the deterioration of, the status of a subject having a demyelinating peripheral neuropathy comprising administering to the subject an effective amount of a compound having a structure defined in  claim 1 . 
     
     
         16 - 19 . (canceled) 
     
     
         20 . A pharmaceutical formulation comprising a compound having a structure defined in any of  claims 1  in combination with at least one further therapeutic agent useful for treating a patient having a demyelinating peripheral neuropathy. 
     
     
         21 . A formulation of  claim 20 , wherein the at least one further therapeutic agent is selected from an immunosuppressant (e.g., cyclosporin A, cyclosporin G, FK-506, ABT-281, ASM981, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin, a corticosteroid, cyclophosphamide, azathioprine, methotrexate, leflunomide, mizoribine, mycophenolate mofetil, or 15-deoxyspergualine), a steroid (e.g., prednisone or hydrocortisone), an immunoglobulin, or type 1 interferon. 
     
     
         22 . A compound having a structure defined in  claims 1  for simultaneous, separate or sequential co-administration with at least one further agent as defined in  claim 21 .